Abstract for Project 3 (Gao and Sumer) Immune checkpoint inhibitors (e.g. Keytruda) have achieved remarkable success in cancer treatment and are becoming a key component of cancer care. However, the majority of patients still fail to respond to checkpoint blockade therapy due to inadequate anti-tumor immunity. The goal of this Project is to establish a nanoengineering strategy for spatio-temporally coordinated delivery of innate and adaptive immune modulators to mount a robust anti-tumor immunity against solid cancers. We will test the hypothesis that implementation of an ultra-pH sensitive (UPS) nanoparticle delivery platform for immunomodulator delivery will achieve potent intratumoral immune activation with improved safety profiles compared to current treatments. The UPS technology allows us to synergize our efforts with Dr. Zhijian ?James? Chen (Project 1) and Dr. Yang-Xin Fu (Project 2). Together, we will establish a synergistic nano-immuno-oncology strategy to overcome tumor immune evasion. We will carry out the following Specific Aims: (1) Investigate biodegradable ultra-pH sensitive NPs for site-specific delivery of innate and adaptive immunomodulators; (2) Engineer a CD47p-encoded ultra-pH sensitive NP system with reduced uptake in the liver and spleen; (3) Evaluate the therapeutic synergy of combination therapy using immunomodulator loaded, CD47- functionalized nanoparticles. The pH sensitive nanoparticles offer a versatile platform technology to fine tune and coordinate innate sensing and adaptive responses in our envisioned immune engineering and reprogramming scheme. By selecting cGAS-STING at the confluence of innate and adaptive immunity and simultaneously altering the cytokine profile of tumors, we will create a new paradigm for cancer immunotherapy by targeting key molecular, cellular and tumor microenvironment signals to generate and sustain a robust anti-tumor immunity.